KR102450460B1 - Mass production system of microsphere drug using ultrasonic nebulizer - Google Patents

Abstract

Provided is a mass production system for polymer-drug microspheres using an ultrasonic nebulizer. Polymer-drug microsphere mass production system according to an embodiment of the present invention, a main supply unit including a first chemical supply unit and a first polymer supply unit; an ultrasonic nebulizer connected to the main supply unit to receive a mixed solution of a chemical and a polymer to form and spray the polymer-drug microspheres; A PVA aqueous solution is stored therein, and the polymer-drug microspheres sprayed from the ultrasonic atomizer are accommodated, and a predetermined polymer-a water tank having an opening through which the drug microspheres can be selectively discharged; a subdivision container for accommodating the polymer-drug microspheres discharged from the opening of the water tank; and a drying unit for drying the PVA aqueous solution remaining in the sub-container.

Description

Mass production system of microsphere drug using ultrasonic atomizer

The present invention relates to a system for producing a microsphere drug having a drug encapsulated in a carrier made of a biodegradable polymer using an ultrasonic nebulizer. In particular, it relates to a system for mass-producing drugs through a continuous process.

In general, protein drugs have low bioavailability. Therefore, in order to improve the bioavailability of protein drugs, considerable efforts have been made to maintain and control the release amount in vivo for a long period of time by using various routes of administration, including oral administration and pulmonary and parenteral injection. Long-term protein delivery in vivo can reduce the frequency of protein administration and increase patient compliance.

Among the developed administration methods, microencapsulation improves protein stability and shows the ability to selectively entrap proteins in a polymer matrix. Thus, sustained protein drug delivery systems using microcapsule reservoirs offer a number of potentially important clinical advantages, including significantly reduced dosing frequency and improved efficacy without toxicity. In addition, when used in vivo, microcapsules can prevent immune recognition of encapsulated proteins, thus overcoming major obstacles to protein administration. At this time, the microcapsule delivery system should have a particle size of less than 100 μm in diameter. This is because particles in this size range tend to remain at the injection site after subcutaneous or intramuscular administration, resulting in slower drug release and less pain.

To date, many microencapsulation techniques have been developed to encapsulate proteins in microcapsules, including emulsion phase separation, double emulsion evaporation, spray drying, and the like. However, double emulsions are usually prepared by mechanical stirring, homogenization or sonication, which can impair or destroy protein function. This method also tends to produce microcapsules with a very wide size distribution as it does not provide fine tuning. This lack of uniformity can cause many problems such as low bioavailability, reduced drug encapsulation efficiency, and reduced reproducibility. In addition, the harsh processing conditions that occur during the microencapsulation process make it difficult to maintain the functional integrity of the encapsulated protein.

Therefore, there was a need to develop a novel microencapsulation technique that can encapsulate proteins using simple procedures and mild conditions to reduce exposure of encapsulated proteins to harmful environments. Accordingly, as a recent technology, coaxial nozzle ultrasonic nebulizers have become a simple and highly efficient means of generating reservoir-type microcapsules using mild conditions. The resulting microcapsules are spherical, small in size, and offer an optimal surface-to-volume ratio and optimal diffusion capacity. It is also more stable than conventional encapsulated proteins of conventional methods to short exposure to stressful conditions. Following the successful application of the coaxial nozzle ultrasonic atomizer, various parameter conditions for the formation of complete microcapsules have been studied.

Along with such research, it is necessary to develop a system for mass-producing actual microcapsules.

An object of the present invention is to provide a system for producing a microsphere drug having a form in which a drug is encapsulated in a carrier made of a biodegradable polymer using a single-axis ultrasonic nebulizer. In particular, it is to provide a mass-production system capable of mass-producing drugs through a continuous process.

The present invention is not limited thereto, and other objects not mentioned will be clearly understood by those skilled in the art from the following description.

According to one aspect of the present invention, a polymer-drug microsphere mass production system in which a drug is encapsulated in a biodegradable polymer carrier, a main supply unit including a first chemical supply unit and a first polymer supply unit, is connected to the main supply unit and is connected to the drug solution and the polymer An ultrasonic nebulizer that forms and sprays the polymer-drug microspheres by receiving a mixture of A polymer-drug microsphere comprising a water tank having an opening for discharging, a sub-container for accommodating the polymer-drug microspheres discharged from the opening of the water tank, and a drying unit for drying the PVA aqueous solution remaining in the sub-container A mass production system may be provided.

At this time, the water tank minimizes air flow, and includes a mixer for stirring the PVA aqueous solution containing the polymer-drug microspheres, and a funnel-shaped water tank discharge part for discharging the stirred solution by the mixer, and discharge the water tank The opening is formed at the lower end of the unit, and may include a first valve installed in the opening.

In this case, the sub-container may include a plurality of sub-containers, and may further include a conveyor belt for moving the plurality of sub-containers so that the plurality of sub-containers pass sequentially under the opening.

In this case, the polymer produced through the drying unit may further include a packaging unit for packaging the plurality of sub-containers containing the drug microspheres.

At this time, further comprising an auxiliary supply unit comprising a second chemical supply unit and a second polymer supply unit, wherein the auxiliary supply unit is connected in parallel with the main supply unit to the ultrasonic atomizer, the main supply unit is the chemical solution and the polymer mixture When not supplied to the ultrasonic nebulizer, it is possible to supply a mixture of the chemical and the polymer to the ultrasonic nebulizer.

At this time, the ultrasonic nebulizer may consist of a single tube in which the mixed liquid of the chemical and the polymer passes.

At this time, the water tank discharge part is located above the first valve, and the PVA aqueous solution passes through and the polymer-drug microspheres are filtered. and a second valve installed in the middle of the water tank discharge unit to form an upper boundary of the loading unit.

On the other hand, the sub-container is installed inside the sub-container and has a cone-shaped bottom plate whose radius becomes narrower toward the bottom, a hole formed in the center of the bottom plate to allow a solution to pass through, and the PVA located at the top of the hole. A filter for a subdivision container that passes the aqueous solution and filters the polymer-drug microspheres, and a subdivision container discharge part that is installed to be connected from the hole to one side of the subdivision container, and discharges the PVA aqueous solution that has passed through the filter can

At this time, it may further include a water channel located on one side of the conveyor belt to collect the PVA aqueous solution discharged through the subdivision container discharge unit.

According to an embodiment of the present invention, in the manufacture of a microsphere drug having a drug encapsulated in a carrier made of a biodegradable polymer, a large amount of a drug solution and a large amount of polymer are added to the target through one single and continuous process It can be provided with a system for mass-producing the drug.

The effects of the present invention are not limited to the above-described effects, and the effects not mentioned will be clearly understood by those of ordinary skill in the art to which the present invention belongs from the present specification and accompanying drawings.

The present invention will be described in detail with reference to the drawings below, but since these drawings show preferred embodiments of the present invention, the technical spirit of the present invention should not be construed as being limited only to the drawings.
1 is a schematic diagram of a configuration for forming polymer-drug microspheres using an ultrasonic nebulizer according to an embodiment of the present invention.
2 is an overall schematic diagram of a polymer-drug microsphere mass production system according to an embodiment of the present invention.
3 is a schematic diagram of a polymer-drug microsphere mass production system including a first valve, a water tank filter, and a second valve installed in a water tank and a water tank outlet according to a first embodiment of the present invention.
4 is a cross-sectional view of a subdivision container according to a second embodiment of the present invention.
5 is a schematic diagram of a polymer-drug microsphere mass-production system including a subdivision container, a conveyor belt, and a water channel according to a second embodiment of the present invention.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. The following examples are presented in order to sufficiently convey the spirit of the present invention to those of ordinary skill in the art to which the present invention pertains. The present invention is not limited to the embodiments presented herein, and may be embodied in other forms. The drawings may omit the illustration of parts irrelevant to the description in order to clarify the present invention, and may slightly exaggerate the size of the components to help understanding.

The present invention provides a system capable of continuously manufacturing a large amount of drugs in a desired unit packaging capacity by injecting various types of biodegradable polymers and drugs to be encapsulated in polymer solutions. The polymer and the drug may be injected at different injection rates, and the drug of the desired formulation may be mass-produced while varying the concentration of the additive, the ultrasonic strength, the polymer concentration, and the like.

Specifically, the liquid supplied to the main supply unit and the auxiliary supply unit is two or more liquids for the production of polymer-drug microspheres having different compositions of one or more components among biodegradable polymers, drugs, additives and solvents, and preferably in a solution state. When the drug is dissolved in a solvent in which the biodegradable polymer is dissolved, it may be in a single solution phase, and if the drug is insoluble, it may be in two solution phases.

The term "biodegradable polymer" used in the present invention refers to polylactide (PLA), polyglycolide (PGA), or a copolymer thereof, poly(lactide-co-glycolide) (Polylactide-co). -glycolide, PLGA) and its star polymer, poly(lactide-co-glycolide)-glucose (Polylactide-co-glycolide-glucose, PLGA-glucose), polyester, polyorthoester ), polyanhydride, polyamino acid, polyhydroxybutyric acid, polycaprolactone, polyalkylcarbonate, and synthetic polymers such as lipids, fatty acids and waxes and natural polymers such as lipids including derivatives thereof. The above-described biodegradable polymer is only given as an example to help the understanding of the present invention, and is not intended to limit the present invention.

Among the above biodegradable polymers, in particular, polyester series such as PLA, PGA, and PLGA are hydrolyzed in the body and metabolized to lactic acid and glycolic acid, which are harmless to the human body, and biocompatibility and stability are recognized. According to the molecular weight, the ratio of the two monomers, the hydrophilicity, etc., it can be variously adjusted from as short as 1-2 weeks to as long as 1-2 years. can be preferably used for In particular, polyester-based polymers such as PLGA and PLA may be more preferably used in the present invention.

"Drugs" applicable to the present invention include dementia treatment drugs, central nervous system drugs, anticancer agents, antibiotics, antipyretics, analgesics, anti-inflammatory agents, sedatives, antiulcer agents, antidepressants, antiallergic agents, antidiabetic agents, hyperlipidemia agents , anti-tuberculosis agents, hormones, bone metabolism agents, immunosuppressants, angiogenesis inhibitors, contraceptives, vitamins, bioactive peptides and proteins, but are not limited thereto. Drugs such as dementia treatment drugs or central nervous system drugs can be more preferably applied to the present invention.

1 is a schematic diagram of a configuration for forming polymer-drug microspheres using an ultrasonic nebulizer 20 according to an embodiment of the present invention. 2 is an overall schematic diagram of a polymer-drug microsphere mass production system according to an embodiment of the present invention.

According to an embodiment of the present invention, the mass production system of the polymer-drug microspheres in which the drug is encapsulated in the biodegradable polymer carrier is the main supply unit 10, the ultrasonic atomizer 20, the water tank 30, the subdivision container 40 and the drying system. A portion 50 may be included.

The main supply unit 10 may be composed of a first chemical solution supply unit 14 for supplying a large amount of chemical material and a first polymer supply unit 15 for supplying a large amount of polymer material. The main supply unit 10 is connected to the ultrasonic nebulizer 20 to supply a mixture of a chemical and a polymer to the ultrasonic nebulizer 20 . The main supply unit 10 may include a valve 38 for controlling the flow rate of the mixed solution when connected to the ultrasonic atomizer 20 . At this time, the valve 38 may be electronically controlled. The first chemical solution supply unit 14 and the first polymer supply unit 15 may each be provided with a flow rate control device (not shown) capable of adjusting the supply flow rate. By varying each flow rate, a drug having a different composition of the desired polymer-drug microspheres can be produced.

The ultrasonic atomizer 20 may receive a mixture of a chemical and a polymer from the main supply unit 10 . Referring to the enlarged view of Figure 1, the ultrasonic atomizer 20 may form a tube 24 therein, may be provided with a spray nozzle 26 at the lower portion. Ultrasonic vibration may be applied to the mixed solution while passing through the tube 24 inside the ultrasonic atomizer 20 . A liquid mixture of a chemical and a polymer may be sprayed by ultrasonic vibration to form micro-sized liquid crystals. More specifically, the micro-liquid crystal may have a spherical shape as a whole, and the polymer may have an overall spherical body, in which a plurality of microspheres of a chemical solution having a smaller size are encapsulated therein. On the other hand, the ultrasonic nebulizer 20 may include an ultrasonic control unit 22 that can adjust the intensity and duration of the ultrasonic waves.

Referring to FIG. 2 , the water tank 30 may be located below the spray nozzle 26 of the ultrasonic atomizer 20 . At this time, the upper inlet of the water tank may be closed by engaging the spray nozzle 26 of the ultrasonic atomizer 20 . The water tank 30 may accommodate the polymer-drug microspheres sprayed from the ultrasonic nebulizer 20 . At this time, the PVA aqueous solution may be stored inside the water tank 30 before the polymer-drug microspheres are injected. Preferably, the interval between the upper surface of the PVA aqueous solution stored in the water tank 30 and the injection nozzle 26 may be 1 cm. The water tank 30 may be provided with an opening 31 through which a predetermined polymer-drug microsphere mixed PVA aqueous solution can be selectively discharged at a lower portion thereof.

The subdivision container may be located under the opening 31 of the water tank 30 . Accordingly, the subdivision container 40 can accommodate the polymer-drug microspheres discharged from the opening 31 .

The drying unit 50 may be supplied with a subdivision container 40 for accommodating the polymer-drug microspheres. Accordingly, the drying unit 50 may provide a function of volatilizing and drying the PVA aqueous solution included with the polymer-drug microspheres in the subdivision container 40 .

Meanwhile, the water tank 30 may further include a mixer 36 , a water tank discharge unit 37 , and a first valve 32 .

The mixer 36 is located inside the water tank 30 and provides a function of stirring the PVA aqueous solution containing the polymer-drug microspheres. Accordingly, the polymer-drug microspheres can be uniformly distributed in the PVA aqueous solution.

The water tank discharge part 37 is located at the lower end of the water tank 30 and may have a funnel shape. This provides the function of discharging the solution stirred by the mixer 36 .

Meanwhile, the opening 31 may be formed at the lower end of the water tank discharge unit 37 located at the lower end of the water tank 30 .

The first valve 32 may be installed in the opening 31 . The first valve 32 provides a function of repeating opening and closing so that a predetermined amount of the stirred solution can be discharged to the subdivision container 40 at a time. In this case, the first valve 32 may be configured as an electronic control valve.

Meanwhile, a fluid supply means capable of supplying a fluid into the water tank, for example, the fluid storage tank 4 may be connected to the water tank. A fluid storage tank may supply water to a specific oil, eg water, within the water bath if required. At this time, the type of fluid required in the water tank may be variously changed.

According to an embodiment of the present invention, the polymer-drug microsphere mass production system may further include a plurality of sub-containers 40 and a conveyor belt 70 .

The conveyor belt 70 may be located under the water tank 30 . The conveyor belt 70 provides a function of moving the plurality of sub-containers 40 sequentially through the lower portion of the opening 31 . More specifically, a first step in which one sub-container 40 is located below the opening 31; a second step in which the subdivision container 40 receives the solution discharged from the opening 31; and a third step of moving the completed subdivision container 40 to the next process when the discharging and receiving of the solution is completed once; while the process is in progress, the conveyor belt 70 is provided with a plurality of The subdivision container 40 can be moved.

On the other hand, the polymer-drug microsphere mass production system may further include a packaging unit (60). The packaging unit 60 provides a function of packaging the plurality of subdivision containers 40 containing the polymer-drug microspheres produced by passing through the drying unit 50 .

In addition, the polymer-drug microsphere mass production system may further include an auxiliary supply unit (12). The auxiliary supply unit 12 may be composed of a second chemical solution supply unit 16 for supplying a large amount of chemical material and a second polymer supply unit 17 for supplying a large amount of polymer material. The auxiliary supply unit 12 may be connected in parallel to the ultrasonic atomizer 20 together with the main supply unit 10 . Accordingly, the auxiliary supply unit 12 also supplies a mixture of a chemical and a polymer to the ultrasonic atomizer 20 . The auxiliary supply unit 12 serves to supply the chemical liquid and the polymer mixture to the ultrasonic atomizer 20 when the main supply unit 10 does not supply the chemical liquid and the polymer mixture to the ultrasonic atomizer 20 . Therefore, it is possible to continuously produce the desired polymer-pharmaceutical microspheres without stopping the process. The auxiliary supply unit 12 may include a valve 39 for controlling the flow rate of the mixed solution when connected to the ultrasonic atomizer 20 . In this case, the valve 39 may be electronically controlled. The second chemical solution supply unit 16 and the second polymer supply unit 17 may be provided with a flow rate adjusting device (not shown) capable of adjusting the supply flow rate, respectively. By varying each flow rate, a drug having a different composition of the desired polymer-drug microspheres can be produced.

On the other hand, in the ultrasonic atomizer 20, the tube 24 located therein may be made of a single tube. Accordingly, a solution in which the polymer and the chemical are mixed can be supplied to the single tube at once.

According to the first embodiment of the present invention, the water tank discharge unit may further include a water tank filter 80 , a loading unit, and a second valve 82 .

3 is a polymer-drug microsphere including a first valve 84, a water tank filter 80, and a second valve 82 installed in the water tank 30 and the water tank outlet according to the first embodiment of the present invention. It is a schematic diagram of the mass production system.

Referring to FIG. 3 , the water tank filter 80 may be located above the first valve 84 . The water tank filter 80 may provide a function of passing the PVA aqueous solution and filtering the polymer-drug microspheres.

The loading part may mean a space having a certain volume located above the water tank filter 80 in the water tank discharge part. The loading unit may provide a storage space corresponding to a preset unit packaging capacity on the water tank filter 80 .

The second valve 82 may be installed in the middle of the water tank discharge part. More specifically, an upper boundary of the loading part may be formed. Accordingly, it functions to provide a solution to the loading unit by the unit packaging capacity at each opening and closing once.

Meanwhile, the water tank discharge unit may further include a PVA aqueous solution discharge unit (not shown), and a polymer-drug microsphere discharge device (not shown).

According to the first embodiment of the present invention, a one-time process of the water tank discharge unit will be described in detail as follows. First, in a state in which both the first valve 84 and the second valve 82 are closed, the first valve 84 is opened to allow the polymer-pVA aqueous solution uniformly containing drug microspheres to flow from the water tank 30 to the loading part. make it When the solution is fully introduced into the loading part, the first valve 84 is closed. After that, when the second valve 82 is opened, only the PVA aqueous solution can be discharged through the PVA aqueous solution outlet through the water tank filter 80 . At this time, the subdivision container 40 is located under the opening 31 in a hollow state. All of the PVA aqueous solution is discharged and the polymer-drug microspheres may remain on the water tank filter 80 by unit packaging capacity. The polymer-drug dispensing device discharges the polymer-drug microspheres remaining on the water tank filter 80 to the subdivision container 40 . After completing the one-time process in this way, the conveyor belt moves the new subdivision container 40 , the first valve 84 and the second valve 82 are all closed, and the next process is performed again.

The first embodiment of the present invention has been described above. At this time, according to the second embodiment of the present invention, the shape of the subdivision container may be formed differently from the first embodiment. Hereinafter, the second embodiment will be described with different drawings.

4 is a cross-sectional view of the subdivision container 40 according to the second embodiment of the present invention. In the second embodiment of the present invention, the subdivision container 40 may further include a bottom plate 46 , a hole, a subdivision container filter 42 and a subdivision container discharge part 44 .

Referring to FIG. 4 , the bottom plate 46 may have a conical shape that is installed inside the subdivision container 40 and has a radius that is narrower toward the bottom. This may provide a function of discharging the PVA aqueous solution more efficiently when the polymer-drug microspheres are filtered in the subdivision container 40 .

The hole may be positioned at the center of the bottom plate 46 to allow the solution to pass therethrough.

The filter for subdivision container 42 is located at the top of the hole to pass the PVA aqueous solution and provide a function of filtering the polymer-drug microspheres.

The subdivision container discharge part 44 is installed to be connected from the hole to one side of the subdivision container 40 , and may provide a function of discharging the PVA aqueous solution that has passed through the subdivision container filter 42 .

According to the second embodiment of the present invention, a one-time process of the water tank 30 will be described in detail as follows. Referring to FIG. 2 , the single sub-container 40 may be positioned under the opening 31 of the water tank 30 . At this time, by opening and closing the electronically controlled first valve 32 , the PVA aqueous solution uniformly containing the polymer-drug microspheres as much as the unit packaging capacity may be discharged from the opening 31 into the subdivision container 40 . At the same time that the solution is accommodated in the subdivision container 40 , the PVA aqueous solution passes through the subdivision container filter 42 and is discharged out of the subdivision container 40 . Successively, the next sub-container 40 may be positioned under the opening 31, and the next one-time process is started.

5 is a schematic diagram of a polymer-drug microsphere mass production system including a subdivision container 40, a conveyor belt 70, and a water channel 72 according to a second embodiment of the present invention.

According to an embodiment of the present invention, the polymer-drug microsphere mass production system may further include a water channel 72 . The water channel 72 may be located on one side of the conveyor belt 70 to provide a function of collecting the PVA aqueous solution discharged through the subdivision container discharge unit 44 .

In one embodiment of the present invention, PLGA (lactic/glycolic acid = 50/50, MW = 14,500) may be used as the biodegradable polymer. BSA-FITC may be used as a desired protein solution. Polyvinyl alcohol (PVA, 87-89% hydrolyzed, MW = 85,000 to 124,000) can also be used as an emulsifier.

The ultrasonic nebulizer 20 for microencapsulation may use a single-axis nozzle ultrasonic nebulizer (Sono-Tek Corp, Milton, NY).

The configuration and effect of the present invention will be described in more detail through the following examples, and the technical scope of the present invention is not limited only to the following examples.

Example 1: Preparation of microspheres encapsulated in fat-soluble dexamethasone using a single-axis ultrasonic sprayer (solvent conditions)

Preparation of microspheres using methylene chloride (MC) as a solvent

Polylactide-co-glycolic acid (PLGA, poly(lactic-co-glycolic acid)) having a molecular weight of 33,000 g/mol was dissolved in methylene chloride (MC, Methylene chloride) to 3% by weight, and fat-soluble dexamethasone ( Dexamethasone) was dissolved in 1 wt% to prepare a uniform drug dispersion solution. After putting this solution in a syringe, it was flowed into a single-axis ultrasonicator at room temperature at a flow rate of 4 mL/min. A 0.5 wt% aqueous solution of polyvinyl alcohol (PVA, polyvinyl alcohol) aqueous solution, 250 mL, was prepared, and the drug dispersion solution was sprayed at a vibration frequency of 60 Hz to disperse in the polyvinyl alcohol aqueous solution to form microspheres. After stabilization by stirring at 700 rpm at room temperature for 2 hours, distilled water was added to the resulting microspheres, washed 4 to 5 times, and freeze-dried to obtain microspheres encapsulated in anhydrous aripiprazole.

Preparation of microspheres using ethyl acetate (EA) as a solvent

Microspheres encapsulated with fat-soluble dexamethasone were prepared in the same manner as in Example 1-1, except that ethyl acetate (EA, Ethyl acetate) was used instead of methylene chloride (MC) as the solvent of Example 1-1.

Preparation of microspheres using ethyl acetate (EA) and dimethyl sulfur monoxide (DMSO) as solvents

Polylactide-co-glycolide (PLGA, poly(lactic-co-glycolic acid)) having a molecular weight of 33,000 g/mol was dissolved in ethyl acetate (EA, Ethyl acetate) to 3% by weight, and fat-soluble dexamethasone ( Dexamethasone) was dissolved in 1 wt% of dimethyl sulfoxide (DMSO) to prepare a uniform drug dispersion solution. After putting this solution in a syringe, it was flowed into a single-axis ultrasonicator at room temperature at a flow rate of 4 mL/min. A 0.5 wt% aqueous solution of polyvinyl alcohol (PVA, polyvinyl alcohol) aqueous solution, 250 mL, was prepared, and the drug dispersion solution was sprayed at a vibration frequency of 60 Hz to disperse in the polyvinyl alcohol aqueous solution to form microspheres. After stabilization by stirring at 700 rpm at room temperature for 2 hours, distilled water was added to the resulting microspheres, washed 4 to 5 times, and freeze-dried to obtain microspheres encapsulated in fat-soluble dexamethasone.

Characterization of Microspheres

5 mg of the microspheres prepared by different solvents of the drug dispersion solution in Examples 1-1 to 1-3 were suspended in distilled water, respectively, and then the size of the microsphere particles was measured using a Zeta potential & particle size analyzer, , the optical microscope image was confirmed. In consideration of the error range, the particle size values and the yield of microspheres measured three times are shown in Table 1 below.

Example 1-1 Example 1-2 Examples 1-3 Particle size (㎛) 77 ± 18 61 ± 24 57 ± 27 transference number (%) 69 83 85

Example 2: Preparation of microspheres encapsulated in fat-soluble dexamethasone using a single-axis ultrasonic injector (temperature conditions)

2-1. Preparation of microspheres at room temperature

Polylactide-co-glycolide (PLGA, poly(lactic-co-glycolic acid)) having a molecular weight of 33,000 g/mol was dissolved in ethyl acetate (EA, Ethyl acetate) to 3% by weight, and fat-soluble dexamethasone ( Dexamethasone) was dissolved in 1 wt% of dimethyl sulfoxide (DMSO) to prepare a uniform drug dispersion solution. After putting this solution in a syringe, it was flowed into a single-axis ultrasonicator at room temperature at a flow rate of 4 mL/min. A 0.5 wt% aqueous solution of polyvinyl alcohol (PVA, polyvinyl alcohol) aqueous solution, 250 mL, was prepared, and the drug dispersion solution was sprayed at a vibration frequency of 60 Hz to disperse in the polyvinyl alcohol aqueous solution to form microspheres. After stabilization by stirring at 700 rpm at room temperature for 2 hours, distilled water was added to the resulting microspheres, washed 4 to 5 times, and freeze-dried to obtain microspheres encapsulated in fat-soluble dexamethasone.

2-2. Microsphere preparation at 30 ^o C

Microspheres encapsulated in fat-soluble dexamethasone were prepared in the same manner as in Example 2-1, except that the temperature at which the drug dispersion solution was injected into the single-axis ultrasonic injector was set to 30 °C in Example 2-1. .

2-3. Microsphere preparation at 35 ^o C

Microspheres encapsulated in fat-soluble dexamethasone were prepared in the same manner as in Example 2-1, except that the temperature at which the drug dispersion solution was injected into the single-axis ultrasonic injector was set to 35 °C in Example 2-1. .

2-4. Microsphere preparation at 40 ^o C

Microspheres encapsulated in fat-soluble dexamethasone were prepared in the same manner as in Example 2-1, except that the temperature at which the drug dispersion solution was injected into a single-axis ultrasonic injector was set to 40 °C in Example 2-1. .

2-5. Microsphere Characterization

5 mg of the microspheres prepared by varying the temperature of the drug dispersion solution in Examples 2-1 to 2-4 were suspended in distilled water, respectively, and then the size of the microsphere particles was measured using a Zeta potential & particle size analyzer, , the optical microscope image was confirmed. The particle size values and the yield of microspheres measured three times in consideration of the error range are shown in Table 2 below.

Example 2-1 Example 2-2 Example 2-3 Example 2-4 Particle size (㎛) 57 ± 27 62 ± 12 61 ± 14 29 ± 28 transference number (%) 85 51 42 41

Example 3: Preparation of microspheres encapsulated in fat-soluble dexamethasone using a single-axis ultrasonic injector (PVA concentration conditions)

3-1. Microsphere preparation at 0.25 wt% PVA concentration

Polylactide-co-glycolide (PLGA, poly(lactic-co-glycolic acid)) having a molecular weight of 33,000 g/mol was dissolved in ethyl acetate (EA, Ethyl acetate) to 3% by weight, and fat-soluble dexamethasone ( Dexamethasone) was dissolved in dimethyl sulfoxide (DMSO) at 3 wt% to prepare a uniform drug dispersion solution. After putting this solution in a syringe, it was flowed into a single-axis ultrasonicator at room temperature at a flow rate of 4 mL/min. 250 mL of a 0.25 wt% aqueous solution of polyvinyl alcohol (PVA, polyvinyl alcohol) aqueous solution was prepared, and the drug dispersion solution was sprayed at a vibration frequency of 60 Hz and dispersed in the polyvinyl alcohol aqueous solution to form microspheres. After stabilization by stirring at 700 rpm at room temperature for 2 hours, distilled water was added to the resulting microspheres, washed 4 to 5 times, and freeze-dried to obtain microspheres encapsulated in fat-soluble dexamethasone.

3-2. Microsphere preparation at 0.5 wt% PVA concentration

Microspheres encapsulated with fat-soluble dexamethasone were prepared in the same manner as in Example 3-1, except that the drug dispersion solution was sprayed at a concentration of 0.5 wt% PVA in Example 3-1.

3-3. Microsphere preparation at 1 wt % PVA concentration

Microspheres encapsulated in fat-soluble dexamethasone were prepared in the same manner as in Example 3-1, except that the drug dispersion solution was sprayed at a concentration of 1 wt% PVA in Example 3-1.

3-4. Microsphere preparation at 2 wt% PVA concentration

Microspheres encapsulated with fat-soluble dexamethasone were prepared in the same manner as in Example 3-1, except that the drug dispersion solution was sprayed at a concentration of 2 wt% PVA in Example 3-1.

3-5. Microsphere Characterization

5 mg of microspheres prepared by varying the PVA concentration of the drug dispersion solution in Examples 3-1 to 3-4 were suspended in distilled water, respectively, and then the size of the microsphere particles was measured using a Zeta potential & particle size analyzer. and the optical microscope image was confirmed. The particle size values and the yield of microspheres measured three times in consideration of the error range are shown in Table 3 below.

Example 3-1 Example 3-2 Example 3-3 Example 3-4 Particle size (㎛) 67 ± 19 76 ± 18 61 ± 20 28 ± 22 transference number (%) 14 80 24 14

Example 4: Preparation of microspheres encapsulated in fat-soluble dexamethasone using a single-axis ultrasonic injector (dexamethasone concentration conditions)

4-1. Preparation of microspheres having a fat-soluble dexamethasone concentration of 3% by weight

Polylactide-co-glycolide (PLGA, poly(lactic-co-glycolic acid)) having a molecular weight of 33,000 g/mol was dissolved in ethyl acetate (EA, Ethyl acetate) to 3% by weight, and fat-soluble dexamethasone ( Dexamethasone) was dissolved in dimethyl sulfoxide (DMSO) at 3 wt% to prepare a uniform drug dispersion solution. After putting this solution in a syringe, it was flowed into a single-axis ultrasonicator at room temperature at a flow rate of 4 mL/min. A 0.5 wt% aqueous solution of polyvinyl alcohol (PVA, polyvinyl alcohol) aqueous solution, 250 mL, was prepared, and the drug dispersion solution was sprayed at a vibration frequency of 60 Hz to disperse in the polyvinyl alcohol aqueous solution to form microspheres. After stabilization by stirring at 700 rpm at room temperature for 2 hours, distilled water was added to the resulting microspheres, washed 4 to 5 times, and freeze-dried to obtain microspheres encapsulated in fat-soluble dexamethasone.

4-2. Preparation of microspheres having a fat-soluble dexamethasone concentration of 2% by weight

Microspheres containing fat-soluble dexamethasone were prepared in the same manner as in Example 4-1, except that the concentration of fat-soluble dexamethasone in Example 4-1 was 2% by weight.

4-3. Preparation of microspheres having a fat-soluble dexamethasone concentration of 1% by weight

Microspheres containing fat-soluble dexamethasone were prepared in the same manner as in Example 4-1, except that the concentration of fat-soluble dexamethasone in Example 4-1 was 1 wt%.

4-4. Microsphere Characterization

5 mg of microspheres prepared by varying the concentration of fat-soluble dexamethasone in Examples 4-1 to 4-3 were suspended in distilled water, respectively, and then the size of the microsphere particles was measured using a Zeta potential & particle size analyzer, , the optical microscope image was confirmed. In consideration of the error range, the particle size values and the yield of microspheres measured three times are shown in Table 4 below.

Example 4-1 Example 4-2 Example 4-3 Particle size (㎛) 76 ± 18 67 ± 24 57 ± 27 transference number (%) 45 44 85

Example 5: Preparation of microspheres encapsulating donepezil (Donepezil base) using a single-axis ultrasonic injector

5-1. Preparation of microspheres using methylene chloride (MC) as a solvent

Polylactide-co-glycolide (PLGA, poly(lactic-co-glycolic acid)) having a molecular weight of 33,000 g/mol was dissolved in methylene chloride (MC, methylene chloride) to 1.95% by weight, and Donepezil base ) was dissolved in 1.05 wt% to prepare a uniform drug dispersion solution. After putting this solution in a syringe, it was flowed into a single-axis ultrasonicator at room temperature at a flow rate of 4 mL/min. A 0.5 wt% aqueous solution of polyvinyl alcohol (PVA, polyvinyl alcohol) aqueous solution, 250 mL, was prepared, and the drug dispersion solution was sprayed at a vibration frequency of 60 Hz to disperse in the polyvinyl alcohol aqueous solution to form microspheres. After stabilization by stirring at 700 rpm at room temperature for 2 hours, distilled water was added to the resulting microspheres, washed 4 to 5 times, and freeze-dried to obtain donepezil-encapsulated microspheres.

5-2. Preparation of microspheres using ethyl acetate (EA) as a solvent

Microspheres encapsulated with donepezil were prepared in the same manner as in Example 5-1, except that ethyl acetate (EA, Ethyl acetate) was used instead of methylene chloride (MC) as the solvent of Example 5-1.

5-3. Microsphere Characterization

After each 5 mg of microspheres prepared by different drug dispersion solutions in Examples 5-1 to 5-2 were suspended in distilled water, the size of the microsphere particles was measured using a Zeta potential & particle size analyzer, and optical Microscopic images were confirmed. In consideration of the error range, the particle size values and the yield of microspheres measured three times are shown in Table 5 below.

Example 5-1 Example 5-2 Particle size (㎛) 45 ± 24 52 ± 19 transference number (%) 70 86

Example 6: Preparation of microspheres encapsulating anhydrous aripiprazole using a single-axis ultrasonic sprayer (solvent conditions)

6-1. Preparation of microspheres using ethyl acetate (EA) as a solvent

Polylactide-co-glycolide (PLGA, poly(lactic-co-glycolic acid)) having a molecular weight of 33,000 g/mol was dissolved in ethyl acetate (EA, Ethyl acetate) to 3% by weight, and anhydrous aripiprazole ) was dissolved in 1% by weight to prepare a uniform drug dispersion solution. After putting this solution in a syringe, it was flowed into a single-axis ultrasonicator at room temperature at a flow rate of 4 mL/min. A 0.5 wt% aqueous solution of polyvinyl alcohol (PVA, polyvinyl alcohol) aqueous solution, 250 mL, was prepared, and the drug dispersion solution was sprayed at a vibration frequency of 60 Hz to disperse in the polyvinyl alcohol aqueous solution to form microspheres. After stabilization by stirring at 700 rpm at room temperature for 2 hours, distilled water was added to the resulting microspheres, washed 4 to 5 times, and freeze-dried to obtain microspheres encapsulated with anhydrous aripiprazole.

6-2. Preparation of microspheres using methylene chloride (MC) as a solvent

Microspheres encapsulated with anhydrous aripiprazole were prepared in the same manner as in Example 6-1, except that methyl chloride (MC) was used instead of ethyl acetate (EA) as a solvent in Example 6-1.

6-3. Characterization of Microspheres

5 mg of microspheres prepared by different drug dispersion solutions in Examples 6-1 to 6-2 were suspended in distilled water, respectively, and then the size of the microsphere particles was measured using a Zeta potential & particle size analyzer, and optical Microscopic images were confirmed. In consideration of the error range, the particle size values and the yield of microspheres measured three times are shown in Table 6 below.

Example 6-1 Example 6-2 Particle size (㎛) 71 ± 23 91 ± 18 transference number (%) 81 88

Example 7: Preparation of microspheres encapsulating water-soluble dexamethasone using a double nozzle ultrasonic sprayer

7-1. Preparation of microspheres using ethyl acetate (EA) distilled water (DW) as a solvent

Polylactide-co-glycolide (PLGA, poly(lactic-co-glycolic acid)) having a molecular weight of 33,000 g/mol was dissolved in ethyl acetate (EA, Ethyl acetate) to 3% by weight, and water-soluble dexamethasone ( Dexamethasone) was dissolved in 1 wt% to prepare a uniform drug dispersion solution. After putting this solution in each syringe, it was flowed into a double nozzle ultrasonicator at a flow rate of 4 mL/min and 0.5 mL/min at room temperature. A 0.5 wt% aqueous solution of polyvinyl alcohol (PVA, polyvinyl alcohol) aqueous solution, 250 mL, was prepared, and the drug dispersion solution was sprayed at a vibration frequency of 60 Hz to disperse in the polyvinyl alcohol aqueous solution to form microspheres. After stabilization by stirring at 700 rpm at room temperature for 2 hours, distilled water was added to the resulting microspheres, washed 4 to 5 times, and freeze-dried to obtain microspheres encapsulated in water-soluble dexamethasone.

7-2. Characterization of Microspheres

After each 5 mg of microspheres prepared by changing the nozzle of the ultrasonic sprayer in Example 7-1 were suspended in distilled water, the size of the microsphere particles was measured using a Zeta potential & particle size analyzer, and the optical microscope image was confirmed. did. In consideration of the error range, the particle size values and the yield of microspheres measured three times are shown in Table 7 below.

Example 7-1 Particle size (㎛) 56 ± 17 transference number (%) 73

Example 8: Preparation of microspheres encapsulating memantine hydrochloride (Memantine HCl) using a double nozzle ultrasonic sprayer (high molecular weight conditions)

8-1. Preparation of microspheres using 20 k polymer

Polylactide-co-glycolide (PLGA, poly(lactic-co-glycolic acid)) having a molecular weight of 20,000 g/mol was dissolved in ethyl acetate (EA, Ethyl acetate) to 3% by weight, and memantine hydrochloride (Memantine) HCl) was dissolved in 4 wt% to prepare a uniform drug dispersion solution. After putting this solution into a syringe, it was flowed into a double nozzle ultrasonicator at room temperature at flow rates of 4 mL/min and 0.5 mL/min, respectively. A 0.5 wt% aqueous solution of polyvinyl alcohol (PVA, polyvinyl alcohol) aqueous solution, 250 mL, was prepared, and the drug dispersion solution was sprayed at a vibration frequency of 60 Hz to disperse in the polyvinyl alcohol aqueous solution to form microspheres. After stabilization by stirring at 700 rpm at room temperature for 2 hours, distilled water was added to the resulting microspheres, washed 4 to 5 times, and freeze-dried to obtain microspheres encapsulated with memantine hydrochloride.

8-2. Preparation of microspheres using polymers of 33 k

Microspheres encapsulated with memantine hydrochloride were prepared in the same manner as in Example 8-1, except that 33 k was used instead of 20 k as the polymer of Example 8-1.

8-3. Preparation of microspheres using a 50 k polymer

Microspheres encapsulated with memantine hydrochloride were prepared in the same manner as in Example 8-1, except that 50 k was used instead of 20 k as the polymer of Example 8-1.

8-4. Preparation of microspheres using 90 k polymers

Microspheres encapsulated with memantine hydrochloride were prepared in the same manner as in Example 8-1, except that 90 k was used instead of 20 k as the polymer of Example 8-1.

8-5. Characterization of Microspheres

The yields of microspheres prepared by varying the molecular weight of the nozzle and the polymer of the ultrasonic sprayer in Examples 8-1 to 8-4 are shown in Table 8 below.

Example 8-1 Example 8-2 Example 8-3 Example 8-4 transference number (%) 70 93 74 66

Example 9: Preparation of microspheres encapsulating memantine hydrochloride (Memantine HCl) using a double nozzle ultrasonic sprayer (dispersion rate conditions of drug dispersion)

9-1. Preparation of microspheres with a dispersion rate of 0.2 mL/min of memantine hydrochloride solution

Polylactide-co-glycolide (PLGA, poly(lactic-co-glycolic acid)) having a molecular weight of 33,000 g/mol is dissolved in ethyl acetate (EA, Ethyl acetate) to 3% by weight, and memantine hydrochloride (Memantine) HCl) was dissolved in 4 wt% to prepare a uniform drug dispersion solution. After putting this solution in a syringe, it was flowed into a double nozzle ultrasonicator at room temperature at flow rates of 4 mL/min and 0.2 mL/min, respectively. A 0.5 wt% aqueous solution of polyvinyl alcohol (PVA, polyvinyl alcohol) aqueous solution, 250 mL, was prepared, and the drug dispersion solution was sprayed at a vibration frequency of 60 Hz to disperse in the polyvinyl alcohol aqueous solution to form microspheres. After stabilization by stirring at 700 rpm at room temperature for 2 hours, distilled water was added to the resulting microspheres, washed 4 to 5 times, and freeze-dried to obtain microspheres encapsulated with memantine hydrochloride.

9-2. Preparation of microspheres with a dispersion rate of 0.5 mL/min of memantine hydrochloride solution

Microspheres encapsulated with memantine hydrochloride were prepared in the same manner as in Example 9-1 when the dispersion rate of the memantine hydrochloride solution of Example 9-1 was 0.5 mL/min instead of 0.2 mL/min.

9-3. Preparation of microspheres with a dispersion rate of 1 mL/min of memantine hydrochloride solution

Microspheres encapsulated with memantine hydrochloride were prepared in the same manner as in Example 9-1 when the dispersion rate of the memantine hydrochloride solution of Example 9-1 was 1 mL/min instead of 0.2 mL/min.

9-4. Preparation of microspheres with a dispersion rate of 1.5 mL/min of memantine hydrochloride solution

Microspheres encapsulated with memantine hydrochloride were prepared in the same manner as in Example 9-1 when the dispersion rate of the memantine hydrochloride solution of Example 9-1 was 1.5 mL/min instead of 0.2 mL/min.

9-5. Characterization of Microspheres

In Examples 9-1 to 9-4, the yields of microspheres prepared by varying the nozzle of the ultrasonic injector and the dispersion rate of the memantine hydrochloride solution are shown in Table 9 below.

Example 9-1 Example 9-2 Example 9-3 Example 9-4 transference number (%) 62 93 82 72

As described above, although the present invention has been described with reference to limited embodiments and drawings, the present invention is not limited thereto, and the technical idea of the present invention and the following by those skilled in the art to which the present invention pertains. Of course, various modifications and variations are possible within the scope of equivalents of the claims to be described.

10: main supply unit 12: auxiliary supply unit
20: ultrasonic atomizer 30: water tank
36: mixer 40: subdivision container
42: filter for subdivision container 44: subdivision container discharge part
50: drying unit 60: packaging unit
70: conveyor belt 72: waterway
80: water tank filter 82: second valve
84: first valve

Claims (9)

As a mass production system of polymer-drug microspheres in which a drug is encapsulated in a biodegradable polymer carrier,
a main supply unit including a first chemical supply unit and a first polymer supply unit;
an ultrasonic nebulizer connected to the main supply unit to receive a mixed solution of a chemical and a polymer to form and spray the polymer-drug microspheres;
A PVA aqueous solution is stored therein, and the polymer-drug microspheres sprayed from the ultrasonic atomizer are accommodated, and a predetermined polymer-a water tank having an opening through which the drug microspheres can be selectively discharged;
a subdivision container for accommodating the polymer-drug microspheres discharged from the opening of the water tank; and
A polymer-drug microsphere mass production system comprising a; a drying unit for drying the PVA aqueous solution remaining in the subdivision container.
The method of claim 1,
The water tank is
a mixer for stirring the PVA aqueous solution containing the polymer-drug microspheres;
It includes a funnel-shaped water tank discharge part for discharging the stirred solution by the mixer,
The opening is formed at the lower end of the water tank discharge part,
A polymer-drug microsphere mass production system comprising a; a first valve installed in the opening.
The method of claim 1,
Polymer-drug microsphere mass production system further comprising a; the sub-container is made of a plurality of sub-containers, and a conveyor belt for moving the plurality of sub-containers so that the plurality of sub-containers pass sequentially under the opening.
The method of claim 1,
The polymer-drug microsphere mass production system further comprising a; a packaging unit for packaging the sub-container containing the polymer-drug microspheres produced through the drying unit.
The method of claim 1,
Further comprising an auxiliary supply unit comprising a second chemical supply unit and a second polymer supply unit,
The auxiliary supply unit is connected in parallel with the main supply unit to the ultrasonic nebulizer, so that when the main supply unit does not supply the chemical solution and the polymer mixture to the ultrasonic nebulizer, a mixture of the chemical and the polymer is supplied to the ultrasonic nebulizer. Polymer-drug microsphere mass production system.
The method of claim 1,
The ultrasonic nebulizer,
A polymer-drug microsphere mass-production system in which the tube formed to pass the chemical solution and the polymer mixture is a single tube.
3. The method of claim 2,
The water tank discharge unit,
a water tank filter positioned above the first valve to pass the PVA aqueous solution and filter the polymer-drug microspheres;
a loading unit provided with a storage space corresponding to a preset unit packaging capacity on the water tank filter; and
A second valve installed in the middle of the water tank discharge unit to form an upper boundary of the loading unit; Polymer-drug microsphere mass production system further comprising a.
4. The method of claim 3,
The subdivision container,
a cone-shaped bottom plate installed inside the sub-container and having a narrower radius toward the bottom;
a hole formed in the center of the bottom plate to allow the solution to pass therethrough;
a filter for subdivision containers positioned at the top of the hole to pass the PVA aqueous solution and filter the polymer-drug microspheres; and
The polymer-drug microsphere mass production system further comprising a; is installed to be connected from the hole to one side of the subdivision container, and a subdivision container discharge unit for discharging the PVA aqueous solution that has passed through the filter.
9. The method of claim 8,
The polymer-drug microsphere mass production system, which is located on one side of the conveyor belt and further includes a water channel for collecting the PVA aqueous solution discharged through the subdivision container discharge part.

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